The renal medulla is the only mammalian tissue exposed to elevated concentrations of urea, a potent denaturant of proteins and nucleic acids that adversely affects cell function. Renal epithelial cells in culture, however, appear to be uniquely capable of responding to hyperosmotic urea with mitogenesis and increased expression of two immediate-early gene (IEG) transcription factors, Egr-1 and c-fos. As such, the overall objective of this project is two-fold: to define the molecular mechanism of urea-induced IEG expression; and to determine whether urea exerts its renal epithelial cell-specific mitogenic effect through IEG-mediated induction and autocrine action of a peptide growth factor or receptor.